Summary: Alzheimer's disease (AD) is associated with degeneration changes and loss of various specific populations of neurons in the brain. Since neurotrophic factors regulate survival and differentiated functions of neurons, they may provide avenues for the development of effective treatment for AD. By preventing or attenuating neuronal degeneration, neurotrophic factors may slow down or stop the progression of the disease and associated cognitive disturbances. Based on its ability to prevent degenerative changes of cholinergic neurons induced by experimental lesions in rats and monkeys, nerve growth factor (NGF) is presently considered as experimental treatment for AD. The value of NGF in the treatment of AD is limited by its selectivity for forebrain cholinergic neurons. NGF homologs, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5), forming the family of neurotrophins, affect many populations of brain neurons. The analysis of their neurotrophic actions is ongoing. They appear to have different, but partially overlapping spectra of activity on select populations of central neurons. Aiming at identifying the most useful neurotrophin molecules, we propose to prepare neurotrophins, neurotrophin mutants, modified neurotrophins, as well as novel neurotrophic factors for this program project. The new molecules will be characterized initially in receptor assays and in cell culture assays. Biologically active molecules selected by the in vitro assays will then be tested in vivo in rat brain lesion models mimicking degenerative changes occurring in AD brains. Models of neurodegeneration to be used include septo-hippocampal cholinergic and GABAergic neurons after fimbrial transection, cortico- hippocampal neurons after transections of the angular bundle, and thalamo-cortical neurons after cingulotomy. Two additional projects are proposed. To assess the therapeutic potential of neurotrophins, we plan to measure the responsiveness of brain tissue to neurotrophins using a novel ex vivo assay. We propose to further analyze the therapeutic potential of the small molecules K-252a and K-252b, compounds earlier shown to potentiate the action of NT-3. It is hoped that the studies will lead to the identification of neurotrophin variants, other neurotrophic factors or small molecules most useful for further development as therapeutics in Alzheimer's disease. The program project joins established academic and industrial scientists with a record of previous collaboration in the pharmacological exploitation of neurotrophic factors for developing effective treatment for AD and cognitive diseases.